The HIV protease is a leading candidate for targeted antiviral drug design because inhibition of this enzyme results in production of non-infectious virions. DMP323, a cyclic urea based protease inhibitor, is an attractive lead compound for an antiviral agent because of its high affinity and specificity for the HIV protease. We have determined the 3D solution structure of the protease/DPM323 complex, determined the protonation states and pKa's of its catalytic aspartyl residues, and characterized the flexibility of the protein and its interactions with solvent molecules. This work is the first comprehensive biophysical characterization of an HIV-1 protease/inhibitor complex in solution. We have also begun a detailed investigation of the protease complexed with a promising, high affinity, peptidomimetic inhibitor, KNI272, currently undergoing clinical trials at the NCI/NIH. The significance of this project arises from the unique, detailed structural information tht we are deriving about HIV protease in solution. This information will contribute improved drug design procedures based upon the understanding of the structure/function relationships of the protein.